Buccal delivery of therapeutic agents is a highly desirable alternative mode of administration for drugs that undergo a significant amount of first pass metabolism when administered orally. Steroids, in particular testosterone, are available in transdermal or transmucosal delivery systems.
Testosterone can be admitted transdermally, transmucosally or in a body cavity using a dosage form such as a patch, implant, film, gel, cream, ointment, or suppository. ANDRODERM® (Watson Labs) and TESTODERM® (Alza Corp.) are exemplary extended release transdermal films. According to its PDR package insert, ANDRODERM drug reservoir layer includes testosterone, alcohol, glycerin, glycerol monooleate, methyl laurate, acrylic acid copolymer and water.
Many researchers have utilized hot-melt extrusion techniques to produce pharmaceutical preparations in various forms. Zhang and McGinity utilized hot-melt extrusion to produce sustained release matrix tablets with poly(ethylene oxide) (PEO) and polyvinyl acetate, and more generally non-film preparations with PEO (Zhang, F. and J. W. McGinity, Properties of Sustained-Release Tablets Prepared by Hot-Melt Extrusion. Pharmaceutical Development and Technology, 1999. 4(2): p. 241-250; Zhang, F. and J. W. McGinity, Properties of Hot-Melt Extruded Theophylline Tablets Containing Poly(Vinyl Acetate). Drug Development and Industrial Pharmacy, 2000. 26(9): p. 931-942; Robinson, J. R., J. W. McGinity, and P. Delmas, Effervevescent granules and methods for their preparation. June 2000 and November 2003, Ethypharm: U.S. Pat. Nos. 6,071,539 and 6,649,186.) Kothrade et al. (Kothrade, S., et al., Method for producing solid dosing forms. 2003: U.S. Pat. No. 6,528,089 WO9927916 DE19753298 EP1035841) demonstrated a method of producing solid dosage forms of active ingredients in a vinyllactam co-polymeric binder by hot-melt extrusion. Aitken-Nichol et al. (Aitken-Nichol, C., F. Zhang, and J. W. McGinity, Hot Melt Extrusion of Acrylic Films. Pharmaceutical Research, 1996. 13(5): p. 804-808) used hot-melt extrusion methods to produce acrylic polymer films containing the active lidocaine HCl. Grabowski et al. (Grabowski, S., et al., Solid active extrusion compound preparations containing low-substituted hydroxypropylcellulose. 1999: U.S. Pat. No. 5,939,099 WO9625151 DE19504832 EP0809488) produced solid pharmaceutical preparations of actives in low-substituted hydroxypropyl cellulose using hot-melt extrusion techniques. Repka and McGinity (Repka, M. A. and J. W. McGinity, Hot-melt extruded films for transmucosal & transdermal dung delivery applications. Drug Delivery Technology, 2004. 4(7): p. 40, 42, 44-47) used hot-melt extrusion processes to produce bioadhesive films for topical and mucosal adhesion applications for controlled drug delivery to various mucosal sites (Repka, M. A., S. L. Repka, and J. W. McGinity, Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof. Apr. 23, 2002: U.S. Pat. No. 6,375,963; Breitenbach, J. and H. D. Zettler, Method for producing solid sphereical materials containing a biologically active substance. 2000: WO 0024382). Robinson et al. produced effervescent granules with controlled rate of effervescence using hot melt extrusion techniques. Breitenbach and Zettler (Breitenbach, J. and H. D. Zettler, Method for producing solid sphereical materials containing a biologically active substance. 2000: WO 0024382) produced solid spherical materials containing biologically active substances via hot-melt extrusion. De Brabander et al. (de Brabander, C., C. Vervaet, and J. P. Remon, Development and evaluation of sustained release mini-matrices prepared via hot melt extrusion. Journal of Controlled Release, 2003. 89(2): p. 235-247; de Brabander, C., et al., Bioavailability of ibuprofen from hot-melt extruded mini-matrices. International Journal of Pharmaceutics, 2004. 271(1-2): p. 77-84) demonstrated sustained release mini-matrices by utilizing hot-melt extrusion techniques.
Various different drugs have been included in HME compositions. Under given circumstances, stable HME compositions can be made. However, the chemical stability of a drug included within the matrix of the HME composition is highly variable when comparing different combinations of matrix-forming material, drugs, excipients and processing conditions.
Various different thermoplastic materials have been used as the matrix-forming material in HME compositions. These materials are generally, but not necessarily, polymeric. One of the more desired polymers for this use is PEO, because PEO-based HME compositions are bioadhesive. They adhere to mucosal tissue when placed in contact with it. Thus, PEO-based HME compositions can be used for transmucosal delivery of therapeutic agents.
U.S. Pat. No. 6,072,100 to Mooney et al. discloses an extruded composition containing “a thermoplastic water-soluble polymer selected from the group consisting of hydroxypropyl cellulose and polyethylene oxide; a water-soluble polymer derived from acrylic acid; medicament; and plasticizer.”
U.S. Pat. No. 6,375,963 to Repka et al. discloses a bioadhesive hot-melt extruded film composition comprising a water swellable or water soluble thermoplastic polymer (such as HPC or PEO) and a bioadhesive polymer (such as polycarbophil, carbopol, a co-polymer of methyl vinyl ether and maleic acid or anhydride, one or more acrylic polymers, one or more polyacrylic acids, copolymers of these polymers, a water soluble salt of a co-polymer of methyl vinyl ether and maleic acid or anhydride, a combination thereof and their salts). In some embodiments, the film contains an organic acid, a superdisintegrant, a super-absorbent and/or an antioxidant.
Even with the significant advances in the art provided by the '963 Patent, PEO may be prone to degradation according to the hot-melt extrusion conditions to which it is exposed. The product literature for POLYOX® (the trademark for polyethylene oxide as sold by Dow Chemical) indicates that BHT and vitamin-E (D-α-tocopheryl) are suitable antioxidants for use in stabilizing hot-melt extruded compositions based upon PEO. Huang et al. (Chinese Pharmaceutical Journal, (2003) 55/6 (463-472) disclose the advantageous use of parabens and BHT in hot-melt extruded films made from PEO. Repka et al. (International Journal of Pharmaceutics, (20 Jul. 2000) 202/1-2, 63-70) disclose the advantageous use of Vitamin E TPGS in hot-melt extruded films made from PEO.
Crowley et al. (Dissertation Abstracts International, (2003) Vol. 65, No. 1B, p. 178. Order No.: AAI3119662. 264 pages; Biomaterials, (November 2002) Vol. 23, No. 21, pp. 4241-4248) disclose the stabilization of hot-melt extruded films containing PEO as the thermoplastic matrix by inclusion of Vitamin-E-TPGS and Vitamin-E-succinate. The use of low molecular weight PEO as a processing aid for high molecular weight PEO is disclosed. They also disclose that ascorbic acid (0.5-1.0%) degrades PEO during hot-melt extrusion suggesting that ascorbic acid should not be included in formulations containing PEO. Crowley et al. do not disclose the use of testosterone or another steroid in the film.
Moreover, a drug included in a HME composition may also be prone to degradation. For example, testosterone is prone to degradation in alkaline conditions. Its major degradants include 6-beta-hydroxytestosterone, 4-Androsten-16-alpha-ol-3,17-dione, Androstenedione, Epi-testosterone. So, if testosterone, or any other alkaline labile drug were to be included in a HME composition, such a composition would necessarily exclude alkaline materials. Alkaline materials often have desirable physical or clinical properties. So their exclusion from HME compositions is not desirable.
It would be an advancement in the art to develop a method of manufacturing a HME composition comprising an alkaline matrix-forming material and an alkaline labile drug.